Processes for preparing darifenacin hydrobromide

ABSTRACT

The invention encompasses processes for the preparation of darifenacin hydrobromide.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.12/151,484, filed May 6, 2008, which is a division of U.S. patentapplication Ser. No. 11/646,919, filed Dec. 27, 2006, which claims thebenefit of priority to U.S. provisional application Ser. No. 60/754,395,filed Dec. 27, 2005; 60/772,250, filed Feb. 9, 2006; 60/776,311, filedFeb. 23, 2006; 60/809,147, filed May 25, 2006; 60/812,579, filed Jun. 8,2006; 60/836,557, filed Aug. 8, 2006; 60/837,407, filed Aug. 10, 2006;60/850,184, filed Oct. 5, 2006; 60/859,332, filed Nov. 15, 2006; and60/873,680, filed Dec. 7, 2006, hereby incorporated by reference. Thisapplication is also related to U.S. application Ser. No. 12/217,264,filed Jul. 1, 2008, entitled “Processes for Preparing DarifenacinHydrobromide;” Ser. No. 11/647,109, filed Dec. 27, 2006, entitled“Processes for Preparing Darifenacin Hydrobromide;” and Ser. No.11/646,915, filed Dec. 27, 2006, entitled “Pure Darifenacin HydrobromideSubstantially Free of Oxidized Darifenacin and Salts Thereof and Processfor the Preparation Thereof,” hereby incorporated by reference.

FIELD OF THE INVENTION

The invention encompasses processes for the preparation of darifenacinhydrobromide.

BACKGROUND OF THE INVENTION

Darifenacin,(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide,a compound having the chemical structure,

is a selective M3 receptor antagonist. Blockade of destructor muscleactivity manifests in an increase in urine volume that the bladder canretain, reduction of urination frequency, and decrease in pressure andurgency associated with the urge to urinate, and thereby episodes ofincontinence are reduced.

Darifenacin is administered as the hydrobromide salt,(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamidehydrobromide, of the structure

and is marketed under the trade name ENABLEX® by Novartis.

U.S. Pat. No. 5,096,890, hereby incorporated by reference, disclosesthree routes for the synthesis of darifenacin hydrobromide; all of whichcomprise the cumbersome and hazardous Mitsunobu reaction, described inthe following Scheme.

Accordingly, 1-tosyl-3-(R)-pyrrolidinol is reacted with methyl tosylate,and with diethylazodicarboxylate (DEAD), a very dangerous reagent.Typically, the product is contaminated with triphenylphosphine oxide,which is very difficult to separate from the desired product. Moreover,other toxic and hazardous reagents, such as pyridine and NaH, are usedin other steps of the synthesis.

The process disclosed in U.S. publication No. 20003/0191176 for thepreparation of Darifenacin hydrobromide requires the use of BF₃, whichis also a toxic reagent.

Therefore, there is a need in the art for a process for the preparationof darifenacin hydrobromide that does not use toxic and dangereousreagents and that can be performed on an industrial scale. The presentinvention provides such processes.

SUMMARY OF THE INVENTION

In one embodiment, the invention encompasses anN-protected-3-(S)-pyrrolidinol of the formula,

wherein X is S, SO₂, Si, or CO, and R is phenyl, tolyl, ortho, meta, orpara-xylyl, linear or branched C₁₋₁₀ alkyl, H, or CF₃.

In another embodiment, the invention encompasses a process for preparingdarifenacin hydrobromide comprising converting theN-protected-3-(S)-pyrrolidinol into darifenacin hydrobromide.

In another embodiment, the invention encompasses a process for preparingdarifenacin hydrobromide comprising: a) combining3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the groupconsisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organicsolvent, and mixtures thereof, a sulfonyl halide, and a base to obtain1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I,

b) reacting the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I with diphenylacetonitrile and an inorganic base in an organicsolvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar aprotic organic solvent, and mixtures thereof toobtain (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile offormula II;

c) reacting the(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrileintermediate of formula II with a bromine acceptor selected from thegroup consisting of phenol and naphthol and an acid to obtain(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

wherein the bromine acceptor is phenol only when the acid is HBr;d) combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile saltof formula III and an inorganic base with a solvent selected from thegroup consisting of water immiscible organic solvent, a polar aproticorganic solvent, water, and mixtures thereof to form a mixture; e)acidifying the mixture; f) heating the mixture; g) basifying themixture; h) combining the mixture with a C₁₋₄ alcohol and L-tartaricacid to obtain 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidinetartrate of formula VI;

i) reacting the 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidinetartrate of formula VI with a compound of the formula V

and a base in a solvent selected from the group consisting of a C₆₋₉aromatic hydrocarbon, a polar organic solvent, water, and mixturesthereof; and j) admixing HBr with the mixture to obtain darifenacinbromide, wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl Y is a leavinggroup selected from the group consisting of I, Cl, mesyloxy, Br,tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy, and Z₁ isan acid.

In another embodiment, the invention encompasses a process for preparing1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I

comprising combining 3-(S)-(+)-hydroxypyrrolidine, a sulfonyl halide,and a base in a solvent selected from the group consisting of a C₆₋₉aromatic hydrocarbon, a polar aprotic organic solvent, and mixturesthereof to obtain 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine,wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl.

In another embodiment, the invention encompasses a process for preparingdarifenacin hydrobromide comprising preparing1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine and converting the1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine into darifenacinhydrobromide.

In another embodiment, the invention encompasses a process for preparing(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil) acetonitrile of formulaII

comprising combining 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I, diphenylacetonitrile, and an inorganic base in an organicsolvent selected from the

group consisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organicsolvent, and mixtures thereof, and an inorganic base to obtain(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile, wherein Xis either C₁₋₁₀ alkyl or C₆₋₉ aryl.

In another embodiment, the invention encompasses a process for preparingdarifenacin hydrobromide comprising preparing(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile andconverting the(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile intodarifenacin hydrobromide.

In another embodiment, the invention encompasses a process for preparing3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartratecomprising: a) combining (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III,

a solvent selected from the group consisting of a water immiscibleorganic solvent, a polar aprotic organic solvent, water, and mixturesthereof, and an inorganic base to form a mixture; b) acidifying themixture; c) heating the mixture; d) basifying the mixture; and e)combining the mixture with a C₁₋₄ alcohol and L-tartaric acid to obtain3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate,wherein Z₁ is an acid.

In another embodiment, the invention encompasses a process for preparingdarifenacin hydrobromide comprising preparing3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate andconverting the 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidinetartrate into darifenacin hydrobromide.

In another embodiment, the invention encompasses a compound of formula V

wherein Y is a leaving group selected from the group consisting of I,Cl, mesyloxy, Br, tosyloxy, trifluoroacetyloxy, andtrifluoromethansulfonyloxy,

In another embodiment, the invention encompasses a process for preparingthe compound of formula V;

comprising: a) combining 2(2,3-dihydrobenzofura-5-yl)-acetic acid, aC₁₋₄ alcohol, and a catalyst to obtain2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester; b) combining the2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester with a reducingagent and a C₄₋₆ alcohol to obtain 2(2,3-dihydrobenzofura-5-yl)-ethanol;and c) combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol with a solventselected from the group consisting of a C₁₋₂ halogenated hydrocarbon,C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, and a substance containing aleaving group selected from the group consisting of Cl, mesyloxy, Br,tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy, to obtainthe compound of formula V, wherein Y is a leaving group selected fromthe group consisting of I, Cl, mesyloxy, Br, tosyloxy,trifluoroacetyloxy, and trifluoromethansulfonyloxy.

In another embodiment, the invention encompasses a process for preparingdarifenacin hydrobromide comprising preparing the compound of formula V

and converting the compound of formula V into darifenacin hydrobromide,wherein Y is a leaving group selected from the group consisting of I,Cl, brosyloxy, Br, mesyloxy, tosyloxy, trifluoroacetyloxy, andtrifluoromethansulfonyloxy.

In another embodiment, the invention encompasses a process for preparinga compound of the formula V,

comprising: a) combining the bisulfite complex of formula X,

water, NaOH, Na₂CO₃, a water immiscible hydrocarbon, and a reducingagent to form a mixture; and b) combining the mixture with a solventselected from the group consisting of a C₁₋₂ halogenated hydrocarbon,C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, a substance containing aleaving group selected from the group consisting of Cl, Br, mesyloxy,brosyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxyto obtain the compound of formula V, wherein Y is a leaving groupselected from the group consisting of I, Cl, brosyloxy, Br, mesyloxy,tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy.

In another embodiment, the invention encompasses a process for preparingdarifenacin hydrobromide comprising preparing the compound of formula V

and converting the compound of formula V into darifenacin hydrobromide,wherein Y is a leaving group selected from the group consisting of I,Cl, brosyloxy, Br, mesyloxy, tosyloxy, trifluoroacetyloxy, andtrifluoromethansulfonyloxy.

In another embodiment, the invention encompasses a process for preparingdarifenacin hydrobromide comprising: a) combining3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate or thefree base derivative of the following formula,

a derivative of ethyl-dihydrobenzofuran of the following formula V,

a solvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar organic solvent, water, and mixtures thereof, and abase to form a mixture; and b) admixing HBr with the mixture to obtaindarifenacin hydrobromide.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses an N-protected-3-(S)-pyrrolidinol of theformula,

wherein X is S, SO₂, Si, or CO, and R is phenyl, tolyl, ortho, meta, orpara-xylyl, linear or branched C₁₋₁₀ alkyl, H, or CF₃. Preferably, X isSO₂. Preferably, R is tolyl.

In one preferred embodiment, X is S, and R is phenyl, such that theN-protected-3-(S)-pyrrolidinol corresponds toN-phenylthio-3-(S)-pyrrolidinol of the structure

In another preferred embodiment, X is S, and R is tolyl, such that theN-protected-3-(S)-pyrrolidinol corresponds toN-Tolylthio-3-(S)-Pyrrolidinol of the structure

The N-tolylthio-3-(S)-Pyrrolidinol may be characterized by a meltingtemperature of about 108° C. to about 112° C. When X is S, and R isxylyl, the N-protected-3-(S)-pyrrolidinol corresponds toN-Xylylthio-3-(S)-pyrrolidinol of the structure

In another preferred embodiment, X is S, and R is linear or branchedC₁₋₁₀ alkyl, such that the N-protected-3-(S)-pyrrolidinol corresponds toN-Alkylthio-3-(S)-Pyrrolidinol of the structure

In another preferred embodiment, X is SO₂, and R is phenyl, such thatthe N-protected-3-(S)-pyrrolidinol corresponds toN-Benzensulfonyl-3-(S)-Pyrrolidinol of the structure

In another preferred embodiment, X is SO₂, and R is tolyl, such that theN-protected-3-(S)-pyrrolidinol corresponds to N-Tosyl-3-(S)-Pyrrolidinolof the structure

In another preferred embodiment, X is SO₂, and R is xylyl, such that theN-protected-3-(S)-pyrrolidinol corresponds toN-Xylylsulfonyl-3-(S)-Pyrrolidinol of the structure

In another preferred embodiment, X is SO₂, and R is linear or branchedC₁₋₁₀ alkyl, such that the N-protected-3-(S)-pyrrolidinol corresponds toN-Alkylsulfonyl-3-(S)-pyrrolidinol of the structure

In another preferred embodiment, X is Si, and R is linear or branchedC₁₋₁₀ alkyl, such that the N-protected-3-(S)-pyrrolidinol corresponds toN-Alkylsilyl-3-(S)-pyrrolidinol of the structure

In another preferred embodiment, X is CO, and R is H, such that theN-protected-3-(S)-pyrrolidinol corresponds toN-Formyl-3-(S)-pyrrolidinol of the structure

In another preferred embodiment, X is CO, and R is CF₃, such that the3-(S)-(+)-hydroxypyrrolidine corresponds toN-protected-3-(S)-pyrrolidinol of the structure

In another preferred embodiment, X is CO, and R is CH₃, such that theN-protected-3-(S)-pyrrolidinol corresponds toN-Acetyl-3-(S)-pyrrolidinol of the structure

The N-protected-3-(S)-pyrrolidinol may be converted into darifenacinhydrobromide.

The invention also encompasses a process for the preparation ofdarifenacin hydrobromide according to the following general scheme:

wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl Y is a leaving groupselected from the group consisting of I, Cl, mesyl, Br, tosyl,trifluoroacetyl, and trifluoromethansulfonyl, and Z is an acid.Preferably, X is a C₆₋₉ aryl, and more preferably tolyl. Preferably, Yis Cl. Preferably, Z is HBr or HCl. The process of the invention allowsone to prepare darifenacin hydrobromide without the need to employ thecumbersome Mitsunobu reaction. In addition, the process can be practicedon an industrial scale with minimum production hazards.

The process comprises: combining 3-(S)-(+)-hydroxypyrrolidine, a solventselected from the group consisting of a C₆₋₉ aromatic hydrocarbon, apolar aprotic organic solvent, and mixtures thereof, a sulfonyl halide,and a base to obtain the intermediate of formula I; reacting theintermediate of formula I with diphenylacetonitrile, and an inorganicbase in an organic solvent selected from the group consisting of a C₆₋₉aromatic hydrocarbon, a polar aprotic organic solvent, and mixturesthereof to obtain the intermediate of formula II; reacting theintermediate of formula II with a bromine acceptor selected from thegroup consisting of phenol and naphthol and an acid to obtain theintermediate of formula III, wherein the bromine acceptor is phenol onlywhen the acid is HBr; combining the intermediate of formula III with aninorganic base in a solvent selected from the group consisting of waterimmiscible organic solvent, a polar aprotic organic solvent, water, andmixtures thereof, acidifying, heating, basifying, combining with a C₁₋₄alcohol and L-tartaric acid to obtain the intermediate of formula VI;and reacting the intermediate of formula VI with a derivative ofethyl-dihydrobenzofuran of the formula V and a base in a solventselected from the group consisting of a C₆₋₉ aromatic hydrocarbon, apolar organic solvent, water, and mixtures thereof, and adding HBr toobtain darifenacin bromide.

The N—O-sulfonation reaction of the present invention is performed usingsolvents that are not hazardous and toxic, as compared to the pyridinethat is used in U.S. Pat. No. 5,096,890. Also, the reaction leads to amuch higher yield (the process of the invention provides darifenacinhydrobromide in 96% yield, while U.S. Pat. No. 5,096,890 reports thepreparation of darifenacin hydrobromide in 75% yield). Moreover, theproduct is isolated very easily from a mixture of toluene and water, ascompared to the difficult isolation performed in U.S. Pat. No.5,096,890, which includes recovering the product by time consumingsteps, such as distillation of pyridine, extractions withdichloromethane, and crystallization from n-propanol. Hence, thesulfonation reaction limits the process from being scaled up.

The intermediate of formula I,1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine

is prepared by a process comprising combining3-(S)-(+)-hydroxypyrrolidine of the following formula,

a solvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar aprotic organic solvent, and mixtures thereof, asulfonyl halide, and a base; wherein X is either C₁₋₁₀ alkyl or C₆₋₉aryl. Preferably, X is C₆₋₉ aryl, and more preferably tolyl.

When X is tolyl, the compound of formula I refers to1-tosyl-3-(S)-(−)-tosyloxypyrrolidine of the following formula.

Typically, the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I is obtained by the above process in a purity of about 95% toabout 99% area by HPLC. The starting material,3-(S)-(+)-hydroxypyrrolidine is commercially available.

Typically, combining the 3-(S)-(+)-hydroxypyrrolidine and the solventprovides a solution. The sulfonyl halide is then added to the solutionto form a mixture. The addition of the sulfonyl halide to the solutionleads to a rise in the temperature of the solution, typically to about35° C. to about 40° C. Preferably, the base is then added to the mixtureto form a reaction mixture, which leads to a second rise in temperature,typically to about 50° C. to about 60° C. Preferably, after the base isadded, the reaction mixture is maintained at a temperature of about 25°C. to about reflux, more preferably, at about 50° C. to about 55° C.Preferably, after addition of the base, the reaction mixture ismaintained for about 2 to about 10 hours, more preferably, for about 4to about 6 hours.

Preferably, the C₆₋₉ aromatic hydrocarbon is toluene or o-, m-, orp-xylene. Preferably, the polar aprotic organic solvent is a C₁₋₁₀halogenated aliphatic hydrocarbon, amide, or sulfoxide. A preferredC₁₋₁₀ halogenated aliphatic hydrocarbon is C₁₋₅ halogenated hydrocarbon,more preferably, dichloromethane (referred to as DCM),1,2,dichloroethane or dichloropentane. Preferably, the amide is C₁₋₂amide, more preferably, either dimethylformamide (referred to as DMF) ordimethylacetamide (referred to as DMA). Preferably, the sulfoxide isC₁₋₄sulfoxide, more preferably, dimethylsulfoxide (referred to as DMSO).The more preferred solvent is toluene.

Optionally, a phase transfer catalyst (referred to as PTC) may be usedto increase the reaction rate. When the solvent is a C₆₋₉ aromatichydrocarbon, preferably, a phase transfer catalyst is used. Preferably,the PTC is added to the solution of 3-(S)-(+)-hydroxypyrrolidine priorto the addition of the sulfonyl halide. Preferably, the PTC is selectedfrom the group consisting of tetrabutylammonium bromide, ALIQUAT®tributylmethylammonium chloride, tetrabutylammonium sulfate, and DMSO,and more preferably tetrabutylammonium bromide.

Preferably, the halide moiety of the sulfonyl halide is selected fromchloride, bromide, and iodide, and more preferably chloride. Preferably,the sulfonyl halide is tosylchloride, mesylchloride, or brosylchloride,and more preferably tosylchloride. Preferably, the sulfonyl halide isadded portion-wise.

Preferably, the base is either an inorganic base or an organic base. Apreferred organic base is selected from the group consisting ofaliphatic and aromatic amines. Preferably, the aliphatic amine istriethylamine, methylmorpholine, or N,N-diisopropylethyl amine. Apreferred aromatic amine is pyridine. The inorganic base is added,preferably, in a form of an aqueous solution. The aqueous solutioncontains, preferably, an alkali base, and more preferably either sodiumhydroxide or potassium hydroxide. Preferably, the base is added slowly,more preferably over about a half an hour to about two hours, and evenmore preferably over about one hour.

The process for preparing1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I may furthercomprise a recovery step. The1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine may be recovered by anymethod known to one of ordinary skill in the art. Such methods include,but are not limited to, adding water to the reaction mixture; coolingthe reaction mixture to obtain a precipitate of the1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine, and filtering theprecipitate from the reaction mixture. Preferably, the addition of waterprovides a suspension. Preferably, the suspension is cooled to atemperature of about 20° C. to about −5° C., and more preferably toabout 5° C. to about 0° C., to induce precipitation of the1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine. Preferably, the cooledsuspension is maintained for at least about one hour, preferably, forabout 1 to about 2 hours, to give a precipitate of1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine. The precipitate is thenfiltered and dried.

The 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I thusobtained may then be converted to darifenacin bromide.

The intermediate of formula II,(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile

is prepared by a process comprising combining1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I,diphenylacetonitrile, an organic solvent selected from the groupconsisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organicsolvent, and mixtures thereof, and an inorganic base; wherein X iseither C₁₋₁₀ alkyl or C₆₋₉ aryl. Preferably, X is C₆₋₉ aryl, and morepreferably tolyl.

When X is tolyl, the compound of formula II refers to(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile of the followingformula.

(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of theformula II is obtained by the above process in a purity of about 95% toabout 99% area by HPLC, and more preferably about 99% to about 100% areaby HPLC.

Typically, combining the diphenylacetonitrile and the organic solventprovides a first mixture. The addition of the inorganic base to thefirst mixture typically causes the temperature of the first mixture torise to about 20° C. to about 40° C., and preferably to about 25° C. toabout 35° C. Preferably, the first mixture is cooled to a temperature ofabout 30° C. to about 15° C., and more preferably to a temperature ofabout 25° C. to about 15° C., prior to the addition of the1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I. Typically,the addition of the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I provides a second mixture. Preferably, the second mixture isheated to a temperature of about 50° C. to about 100° C., and morepreferably to a temperature of about 70° C. to about 75° C. The heatedsecond mixture is maintained, preferably, for about 3 to about 6 hours,and more preferably, for about 4 to about 5 hours.

Preferably, the C₆₋₉ aromatic hydrocarbon is toluene. Preferably, thepolar aprotic organic solvent is either amide or sulfoxide. A preferredamide is C₁₋₂ amide, more preferably, either DMF or DMA. A preferredsulfoxide is C₁₋₄ sulfoxide, more preferably, DMSO. The more preferredorganic solvent is DMF.

Preferably, the inorganic base is either a metal alkoxide or an alkalihydroxide. A preferred metal alkoxide is either sodium tert-butoxide orsodium methoxide. A preferred alkali hydroxide is either sodium orpotassium hydroxide. The more preferred inorganic base is a metalalkoxide, most preferably either sodium or potassium tert-butoxide.

The process for preparing(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of formulaII may further comprise a recovery step. The(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of formulaII may be recovered by adding to the second mixture to a mixture ofwater and a solvent selected from the group consisting of toluene, DCM,ethyl acetate (referred to as EtOAc), butyl acetate (referred to asBuOAc), and n-butanol to form a mixture having an aqueous and an organicphase; separating the aqueous and organic phases; washing the organicphase with water; and concentrating the organic phase under reducedpressure to obtain a concentrated residue. The residue is then cooled toa temperature of about 10° C. to about −10° C., and preferably to about3° C. to about −3° C., to give a precipitate of(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile.

The (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile offormula II thus obtained may then be converted to darifenacin bromide,for example, by the process disclosed in Example 1 of U.S. Pat. No.5,096,890 (reproduced below as Comparative Example 23).

The intermediate of formula III,(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt, is prepared by aprocess comprising heating a mixture comprising the compound of formulaII, a bromine acceptor selected from phenol and naphthol and an acid,wherein the bromine acceptor is phenol only when the acid is HBr.Preferably, the mixture is heated to a temperature of about 80° C. toabout 120° C., more preferably, to about 117° C. to about 120° C.Preferably, the heated mixture is maintained for about 1 hour to about 2hours, more preferably, for about 1 hour to about 1.5 hours. Preferably,the acid is selected from a group consisting of: phosphoric acid,perchloric acid, tribromomethanesulfonic acid, and HBr, more preferably,HBr. When using HBr as the acid, it is added in a form of an aqueoussolution, having a concentration of about 30% to about 60%, morepreferably, of about 48% to about 60%.

The (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula IIImay be recovered by a process comprising cooling the mixture to atemperature of about 30° C. to about 15° C., more preferably, to atemperature of about 30° C. to about 25° C., followed by extracting witha C₁₋₁₀ halogenated aliphatic hydrocarbon, and washing with brine. Theorganic phase is then concentrated under reduce pressure to give aresidue containing the compound of formula III and the solvent.Preferably, the C₁₋₁₀ halogenated aliphatic hydrocarbon is C₁₋₅halogenated hydrocarbon, more preferably, C₁₋₃ halogenated hydrocarbon.Most preferably, the C₁₋₃ halogenated hydrocarbon is selected from thegroup consisting of DCM, chloroform, dichloroethane, 1,1-dichloroethane,and 1,5-dichloropentane.

The residue is then combined with a second solvent selected from thegroup consisting of BuOAc, toluene, acetone, 2-butanone, anddiisopropylether, followed by a complete removal of the C₁₋₁₀halogenated aliphatic hydrocarbon, preferably, by distillation, to givea second residue.

The second residue, containing the compound of formula III and a solventselected form the group consisting of BuOAc, toluene, acetone,2-butanone, and diisopropylether can be purified by a crystallizationprocess from a solvent selected from the group consisting of C₁₋₁₀ester, C₁₋₁₀ ketone, C₁₋₁₀ ether, C₁₋₁₀ aliphatic hydrocarbon, C₆₋₉aromatic hydrocarbon, and mixtures thereof.

Preferably, the C₁₋₁₀ ester is ethylacetate, n-butylacetate,i-butylacetate, or n-propylacetate, more preferably, ethylacetate.Preferably, the C₁₋₁₀ ketone is acetone, 2-butanone,methyl-isobutylketone, or cyclohexanone. A preferred C₁₋₁₀ ether isdiethylether, diisopropylether, dibutylether, or methyl isobutylether.Preferably, the C₁₋₁₀ aliphatic hydrocarbon is pentane, hexanes,heptanes, or petroleum ether. Preferably, the C₆₋₉ aromatic hydrocarbonis toluene or xylenes. Preferably, a mixture of ethyl acetate (EtOAc)and hexane is used.

The intermediate 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidinetartrate of the formula VI,

is prepared by a process comprising combining(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

a solvent selected from the group consisting of water immiscible organicsolvent, a polar aprotic organic solvent, water, and mixtures thereof,and an inorganic base to obtain a mixture; acidifying the mixture;heating the mixture; basifying the mixture; and combining the mixturewith a C₁₋₄ alcohol and L-tartaric acid; wherein Z₁ is an acid.Preferably Z₁ is either HBr or HCl.

Optionally, the free base of the following formula

may be used as a starting material. The free base of formula XI may beobtained by combining (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrilesalt of formula III a solvent selected from the group consisting ofwater immiscible organic solvent, a polar aprotic organic solvent,water, and mixtures thereof, and an inorganic base.

Preferably, the water immiscible organic solvent is either a C₆₋₉aromatic hydrocarbon or a C₁₋₁₀ halogenated aliphatic hydrocarbon.Preferably, the C₆₋₉ aromatic hydrocarbon is toluene, xylenes,i-propylbenzene or styrene, more preferably, toluene. A preferred C₁₋₁₀halogenated aliphatic hydrocarbon is DCM, 2-dichloroethane,1,1-dichloroethane, or 1,5-dichloropentane.

Preferably, the polar aprotic organic solvent is an ester, morepreferably, EtOAc. The more preferred solvent is a mixture of C₁₋₁₀halogenated aliphatic hydrocarbon and water, and most preferably, of DCMand water.

Preferably, the inorganic base is an aqueous solution of an alkali base.A preferred alkali base is an alkali hydroxide, an alkali carbonate, oran alkali bicarbonate. Preferably, the alkali hydroxide is either sodiumhydroxide or potassium hydroxide. Preferably, the alkali carbonate iseither sodium carbonate or potassium carbonate. A preferred alkalibicarbonate is either sodium bicarbonate or potassium bicarbonate. Themore preferred base is alkali hydroxide, most preferably, sodiumhydroxide.

Typically, the acidifying comprises adding an acid to the mixture andheating. Preferably, the mixture is heated to a temperature of about 80°C. to about 110° C., and more preferably to a temperature of about 90°C. to about 100° C. The mixture is maintained, preferably, for about 15to about 20 hours, and more preferably, for about 16 to about 18 hours.

After maintaining, the mixture is basified, preferably, to a pH of about10 to about 13 and more preferably, to a pH of about 11 to about 12.Preferably, the mixture is basified by adding an inorganic base. Theaddition of the base creates a foam, which is then dissolved in the C₁₋₄alcohol and mixed with the L-tartaric acid to provide3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of theformula VI.

Preferably, the acid is a strong acid, more preferably a strong mineralacid, and even more preferably either sulfuric acid or phosphoric acid.Most preferably, the acid is sulfuric acid. Preferably, theconcentration of the acid is of about 75% to about 90%, more preferably,about 80% to about 85%.

The foam may be recovered by cooling the reaction mixture to atemperature of about 30° C. to about 15° C., more preferably, to about25° C. to about 20° C., followed by increasing the pH to obtain amixture having an aqueous phase and an organic phase. The phases areseparated and the aqueous phase is then extracted with a solventselected from the group consisting of DCM, EtOAc, and toluene, followedby washing the resulting combined organic phases with water, andevaporating the solvent.

Preferably, the C₁₋₄ alcohol is methanol, ethanol, isopropanol, orn-butanol, more preferably ethanol, and most preferably 96% ethanol.

The process for preparing3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate offormula VI may further comprise a recovery step. The3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate offormula VI may be recovered by cooling the solution to a temperature ofabout 5° C. to about −5° C., preferably, to about 3° C. to about −3° C.,to induce precipitation of the3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate, followedby filtering the precipitated3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate from thesolution.

The 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate offormula VI thus obtained may then be converted to darifenacin bromide.

According to the process of the invention,3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate offormula VI is reacted with derivatives of ethyl-dihydrobenzofuran of theformula V to obtain darifenacin hydrobromide.

The invention encompasses a compound of formula V;

wherein Y is a leaving group selected from the group consisting of I,Cl, brosyloxy, Br, mesyloxy, tosyloxy, trifluoroacetyloxy, andtrifluoromethansulfonyloxy. Preferably, Y is Cl. When Y is Cl, thecompound of formula V corresponds to5-(2-chloroethyl)-2,3-dihydrobenzo[2,3-b]furan of the following formula.

The derivatives of ethyl-dihydrobenzofuran of the formula V;

are prepared by a process comprising reacting2(2,3-dihydrobenzofura-5-yl)-acetic acid of the formula,

a C₁₋₄ alcohol, and a catalyst to obtain2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester of the formula

combining the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester witha reducing agent, in a C₄₋₆ alcohol to obtain2(2,3-dihydrobenzofura-5-yl)-ethanol of the formula

and combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol, a solventselected from the group consisting of a C₁₋₂ halogenated hydrocarbon,C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, and a substance containing aleaving group selected from the group consisting of Cl, Br, mesyloxy,brosyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxyto obtain the compound of formula V; wherein Y is a leaving groupselected from the group consisting of I, Cl, brosyl, Br, mesyl, tosyl,trifluoroacetyl, and trifluoromethansulfonyl. Preferably Y is Cl.

The starting 2(2,3-dihydrobenzofura-5-yl)-acetic acid is commerciallyavailable.

Preferably, the C₁₋₄ alcohol is selected from the group consisting ofmethanol, ethanol, propanol, and butanol, and more preferably methanol.Optionally, a mixture of solvents may be used. Preferably, the mixtureis that of C₁₋₄ alcohol and toluene, and more preferably of methanol andtoluene.

Preferably, the catalyst is an acid. Preferably, the acid is either anorganic or an inorganic acid selected from the group consisting ofsulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, HCl, HClO₄,and H₃PO₄. More preferably, the acid is an inorganic acid, and even morepreferably a mineral acid, and most preferably sulfuric acid.

The reaction between the 2(2,3-dihydrobenzofura-5-yl)-acetic acid, theC₁₋₄ alcohol and the catalyst may be performed, preferably, withheating. Preferably, the heating is done to a temperature of about 60°C. to about 70° C., and more preferably about 65° C. to about 70° C.Preferably, heating is done for about 1 to about 5 hours, and morepreferably for about 2 to about 3 hours.

The process for preparing the 2(2,3-dihydrobenzofura-5-yl)-acetic acidmethylester may further comprise a recovery step. The2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester may be recovered bya method known to one of ordinary skill in the art. Preferably, the2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester is recovered byadding a base to the reaction mixture comprising2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester; removing thesolvent; adding a C₆₋₉ aromatic hydrocarbon; washing with a basicsolution; and removing the solvent. Preferably, the base is sodiumbicarbonate. Preferably, removing the solvent from the reaction mixtureprovides a residue. Preferably, the addition of a C₆₋₉ aromatichydrocarbon to the residue provides a solution. Preferably, the C₆₋₉aromatic hydrocarbon is toluene. Preferably, the basic solution issodium bicarbonate.

Preferably, the C₄₋₆ alcohol is t-butanol. Preferably, a mixture of C₁₋₄alcohol and C₄₋₆ alcohol is used, instead of the C₄₋₆ alcohol alone.More preferably, the mixture is that of methanol and t-butanol.

Preferably, the reducing agent is a metal hydride. Preferably, the metalhydride is selected from the group consisting of NaBH₄, LiAlH₄, andVITRIDE® sodium dihydro-bis-(2-methoxyethoxy) aluminate. Morepreferably, the reducing agent is NaBH₄.

Combining the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester, thereducing agent, and the C₄₋₆ alcohol provides a suspension. Preferably,the suspension is heated to a temperature of about 65° C. to about 75°C., more preferably, of about 70° C. to about 75° C. Preferably, theC₁₋₄ alcohol is added drop-wise. Preferably, the drop-wise addition isdone over a period of about 2 to about 6 hours, and more preferably overa period of about 5 to about 6 hours. Typically, adding the C₁₋₄ alcoholprovides a mixture. Preferably, the mixture is maintained for a totaltime of about 5 to about 10 hours, and more preferably for about 5 toabout 7 hours. If the reaction is not completed after 5 to about 10hours, a second amount of a reducing agent can be added. Preferably, thereducing agent is added with a C₁₋₄ alcohol. After the addition of thereducing agent and a C₁₋₄ alcohol, the reaction is further maintained,preferably, for about 1 to about 14 hours, more preferably, for about 2to about 3 hours.

The process for preparing the 2(2,3-dihydrobenzofura-5-yl)-ethanol mayfurther comprise a recovery step. The2(2,3-dihydrobenzofura-5-yl)-ethanol may be recovered by any methodknown to one of ordinary skill in the art. Preferably, the2(2,3-dihydrobenzofura-5-yl)-ethanol is recovered by removing thesolvent; adding water and a solvent selected from the group consistingof toluene, dichloromethane, and ethyl acetate to obtain a mixturehaving an aqueous phase and an organic phase; separating the aqueous andorganic phases; extracting the organic phase with water and a solventselected from the group consisting of toluene, dichloromethane, andethyl acetate; extracting the organic phase with water; and removing thesolvent. Preferably, the C₁₋₂ halogenated hydrocarbon isdichloromethane. A preferred C₃₋₆ ester is ethyl acetate,isopropylacetate, butylacetate, or isobutylacetate. Preferably, the C₆₋₉aromatic hydrocarbon is toluene, xylenes, i-propylbenzene, or styrene.The preferred solvent is toluene.

Preferably, the substance containing a leaving group is selected fromthe group consisting of SOCl₂, PCl₃, PCl₅, POCl₃, tosylchloride,mesylchloride, brosylchloride, trifluoroacetyl chloride, andtrifluoromethansulfonyl chloride. Preferably, the substance containing aleaving group is SOCl₂, PCl₃, PCl₅, or POCl₃, more preferably, SOCl₂.Preferably, the substance containing a leaving group is added drop-wise.When the substance containing a leaving group is one of tosylchloride,mesylchloride, brosylchloride, trifluoroacetyl chloride, andtrifluoromethansulfonyl chloride, a base may also be used. Preferably,the base is either an organic or an inorganic base. The organic base maybe, preferably, an aliphatic or aromatic amine. Preferably, thealiphatic amine is triethylamine, ethyldiisopropylamine, orN-methylmorpholine. A preferred aromatic amine is pyridine. Theinorganic base is preferably either an alkali metal hydroxide or analkali metal carbonate. Preferably, the alkali metal hydroxide is sodiumhydroxide, potassium hydroxide, or cesium hydroxide. A preferred alkalimetal carbonate is sodium, potassium, or cesium carbonate. The morepreferred base is an organic base, preferably, triethylamine.

Preferably, combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol with asolvent selected from the group consisting of a C₁₋₂ halogenatedhydrocarbon, C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, a substancecontaining a leaving group provides a mixture. Preferably, the mixtureis heated to a temperature of about 60° C. to about 80° C., morepreferably, of about 60° C. to about 70° C. The mixture is, preferably,maintained, for about 12 to about 20 hours, more preferably, for about15 to about 18 hours.

The process for preparing the derivative of ethyl-dihydrobenzofuran ofthe formula V may further comprise a recovery step. The derivative ofethyl-dihydrobenzofuran of the formula V may be recovered by any methodknown to one of ordinary skill in the art. Preferably, the derivative ofethyl-dihydrobenzofuran of the formula V is recovered by cooling thereaction mixture to a temperature of about 30° C. to about 15° C.,preferably, to about 25° C. to about 20° C., followed by adding thereaction mixture to a basic solution to form a mixture having an aqueousphase and an organic phase; separating the aqueous and organic phases;extracting the aqueous phase with toluene; washing the organic phasewith water; removing the solvent; and decolorizing the obtained residue.Preferably, the basic solution is of sodium bicarbonate. Decolorizationmay be done by any method known to one of ordinary skill in the art,such as using activated charcoal.

The recovered derivative of ethyl-dihydrobenzofuran of formula V may bepurified by crystallization from methanol/water ormethanol/water/acetone. The process comprises dissolving the derivativeof ethyl-dihydrobenzofuran of formula V in methanol, and adding water ora mixture of water and acetone, followed by maintaining for about anhour to about 3 hours to promote crystallization of the derivative ofethyl-dihydrobenzofuran of formula V. The crystallized derivative ofethyl-dihydrobenzofuran of formula V is then filtered, washed and dried.

Preferably, when the starting commercially available acid analogue2,3-dihydrobenzofuran-5-acetic acid

has less than 0.4% area by HPLC of 5-benzofuranacetic acid, the obtained

5-(2-hydroxyethyl)-2,3-dihydrobenzofuran of formula III

has less than 0.5% of 2-(benzofuran-5-yl)ethanol of following formula.

Preferably, the use of the compound of formula III having less than 0.5%area by HPLC of 2-(benzofuran-5-yl)ethanol in a combination with anaromatic hydrocarbon, more preferably, C₆₋₉ aromatic hydrocarbon, mostpreferably toluene, as a solvent, provides ethyl-dihydrobenzofuran offormula V having less than 0.25% ethyl-benzofuran of the followingformula,

as exemplified in Examples 21 and 22 below.

Alternatively, the derivatives of ethyl-dihydrobenzofuran of the formulaV,

are prepared by a process comprising combining a bisulfite complex offormula X,

water, NaOH, Na₂CO₃, a water immiscible hydrocarbon, and a reducingagent to form a mixture comprising of2(2,3-dihydrobenzofura-5-yl)-ethanol; and combining the mixturecomprising of 2(2,3-dihydrobenzofura-5-yl)-ethanol with a solventselected from the group consisting of C₁₋₂ halogenated hydrocarbons,C₃₋₆ esters, and C₆₋₉ aromatic hydrocarbons and a substance containing aleaving group selected from the group consisting of Cl, Br, mesyloxy,brosyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxyto obtain the compound of formula V, wherein Y is a leaving groupselected from the group consisting of I, Cl, brosyl, Br, mesyl, tosyl,trifluoroacetyl, and trifluoromethansulfonyl. Preferably, Y is Cl.

The starting compound of formula X may be prepared by combining2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde, a water immisciblehydrocarbon, and Na₂S₂O₅ to form a mixture of the compound of formula X.Preferably, the water immiscible hydrocarbon is either a C₆₋₉ aromatichydrocarbon or a saturated hydrocarbon. Preferably, the saturatedhydrocarbons are C₅₋₁₀ saturated hydrocarbons, more preferably, pentane,hexanes or heptanes. Preferably, the C₆₋₉ aromatic hydrocarbon istoluene, xylenes, i-propylbenzene, or styrene. The more preferredsolvent is toluene. Na₂S₂O₅ may be used in a solid form or in a form ofan aqueous solution. Preferably, Na₂S₂O₅ is used in a form of an aqueoussolution. Preferably, after the addition of Na₂S₂O₅ the mixture obtainedis maintained at a temperature of about 15° C. to about 35° C., morepreferably, at about 20° C. to about 25° C. Preferably, the mixture ismaintained for about 2 hours to about 4 hours to obtain the compound offormula X. Preferably, NaOH is added to a suspension of the compound offormula X in water to obtain a basic mixture comprising2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde. Preferably, the pH of thebasic mixture is about 9 to about 11, more preferably about 9.5 to about10.5, and even more preferably about 10 to about 10.2.

Preferably, after adjusting the pH, Na₂CO₃ and a water immisciblehydrocarbon are added to obtain a mixture. Preferably, the waterimmiscible hydrocarbon is either a C₆₋₉ aromatic hydrocarbon or asaturated hydrocarbon. Preferably, the C₆₋₉ aromatic hydrocarbon istoluene. Preferably, the saturated hydrocarbons are C₅₋₁₀ saturatedhydrocarbons. A preferred saturated hydrocarbon is either heptane orcyclohexane. The more preferred solvent is toluene, xylenes,i-propylbenzene, or styrene.

Preferably, the mixture is cooled to a temperature of about 20° C. toabout 0° C., more preferably to about 10° C. to about 5° C., prior tothe addition of the reducing agent. Preferably, adding a reducing agentprovides a reaction mixture. Preferably, the reducing agent is selectedfrom the group consisting of NaBH₄, LiAlH₄, and H₂/Pd. A solution orsolid NaBH₄ may be used. Preferably, a solution of NaBH₄ is used.Preferably, the NaBH₄ is in solution in water or an alcohol. Preferably,the alcohol is a C₃₋₆ alcohol, propanol, i-propanol, butanol, i-butanol,amylalcohol, or cyclohexanol. The more preferred solvent is water.

Preferably, the solution of the reducing agent is added drop-wise.Preferably, the drop-wise addition is done over a period of about 0.5hour to about 1.5 hours, and more preferably over about 45 to about 60minutes.

Preferably, a pH of about 9 to about 11, more preferably, about 9.8 toabout 10.2 is maintained during the addition.

Preferably, after the addition of the reducing agent, the temperature israised to about 10° C. to about 25° C., more preferably, to about 15° C.to about 25° C. Preferably, after raising the temperature, the reactionmixture is maintained for about 0.5 hour to about 1.5 hours, morepreferably, for about 1 hour, to obtain the2(2,3-dihydrobenzofura-5-yl)-ethanol.

Preferably, combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol with asolvent selected from the group consisting of a C₁₋₂ halogenatedhydrocarbon, C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, and a substancecontaining a leaving group provides a mixture. Preferably, the mixtureis heated to a temperature of about 60° C. to about 80° C., morepreferably, of about 60° C. to about 70° C. The mixture is, preferably,maintained, for about 12 to about 20 hours, more preferably, for about15 to about 18 hours. Preferably, the heated mixture providesethyl-dihydrobenzofuran of the formula V.

The derivative of ethyl-dihydrobenzofuran of formula V may then beconverted to darifenacin bromide.

Darifenacin hydrobromide is prepared from the3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate offormula VI by a process comprising combining3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate offormula VI or the free base derivative of the formula XI,

a derivative of ethyl-dihydrobenzofuran of the formula V, a solventselected from the group consisting of a C₆₋₉ aromatic hydrocarbon, apolar organic solvent, water, and mixtures thereof, and a base to form amixture; and admixing HBr with the mixture to obtain darifenacinhydrobromide, wherein Y is a leaving group selected from the groupconsisting of I, Cl, brosyl, Br, mesyloxy, tosyloxy, trifluoroacetyloxy,and trifluoromethansulfonyloxy.

The free base derivative of3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate may beobtained by the process described above for the preparation of compoundof formula VI, excluding the last step, wherein C₁₋₄ alcohol andL-tartaric acid are added.

Preferably, the polar aprotic organic solvent is selected from the groupconsisting of an amide, a C₁₋₁₀ halogenated aliphatic hydrocarbon, asulfoxide, an ester, a nitrile, and a ketone. A preferred amide is DMF.A preferred C₁₋₁₀ halogenated aliphatic hydrocarbon is C₁₋₅ halogenatedaliphatic hydrocarbon, more preferably, DCM. Preferably, the sulfoxideis C₂₋₅ sulfoxide, more preferably, DMSO. Preferably, the ester is C₂₋₅ester, more preferably, EtOAc. A preferred ketone is C₃₋₆ ketone, morepreferably, MEK Preferably, the nitrile is C₂₋₄ nitrile, morepreferably, ACN. Preferably, the C₆₋₉ aromatic hydrocarbon is C₆₋₉aromatic hydrocarbon, more preferably, toluene. Preferred mixtures areeither that of toluene and water or that of DCM and water. The morepreferred solvent is water.

The base may be an inorganic base or an organic base. A preferredorganic base is selected from the group consisting of aliphatic andaromatic amines. Preferably, the aliphatic amine is triethylamine,tributylamine, methylmorpholine, or N,N-diisopropylethyl amine.Preferably, the aromatic amine is pyridine. A preferred inorganic baseis either alkali carbonate or alkali bicarbonate. Preferably, the alkalicarbonate is sodium carbonate or potassium carbonate. Preferably, thealkali bicarbonate is either sodium bicarbonate or potassiumbicarbonate. The most preferred base is an alkali carbonate, even mostpreferably, potassium carbonate.

Preferably, the mixture is heated to a temperature of about 50° C. toabout reflux, and more preferably to a temperature of about 60° C. toabout reflux, prior to admixing with HBr. Preferably, the mixture ismaintained, under heating, for about 1 to about 5 hours, and morepreferably for about 2 to about 3 hours. After maintaining the mixture,the mixture is cooled to a temperature of 35° C. to about 15° C., andpreferably to about 25° C. to about 15° C. Preferably, after cooling, anorganic solvent selected from the group consisting of DCM, EtOAc, andbutyl acetate is added to the mixture, to give a mixture having anaqueous phase and an organic phase. The phases are then separated, andHBr is admixed with the organic phase. Preferably, HBr is added to theorganic phase.

Preferably, a small amount of an anhydride may be added to the organicphase, after separating the phases, followed by maintaining for about 1to about 3 hours. After maintaining, the organic solvent is removed, anda C₂₋₅ alcohol and hydrobromic acid are added, to obtain darifenacinhydrobromide. Preferably, the C₂₋₅ alcohol is n-butanol, sec-butanol,ethanol, 2-methyl-2-butanol, or isopropanol, more preferably, n-butanol.

Darifenacin hydrobromide may be recovered by removing the residual waterand the organic solvent from the acidic mixture obtained after theaddition of HBr, preferably, by distillation under vacuum, to induceprecipitation of the darifenacin hydrobromide. The mixture is thencooled to room temperature and the resulting precipitate of darifenacinhydrobromide is separated from the mixture by filtration.

Darifenacin hydrobromide may be further purified by crystallizing therecovered precipitate from a C₂₋₅ alcohol. The process comprisessuspending the precipitate in a C₂₋₅ alcohol, heating the suspension toa temperature sufficient to induce dissolution of the darifenacinhydrobromide, and cooling the resulting solution to inducecrystallization of the darifenacin hydrobromide. Prior to cooling, thesolution may be purified with active charcoal. The crystallized productmay be isolated by filtration, washing and drying. Preferably, the C₂₋₅alcohol is n-butanol, sec-butanol, ethanol, 2-methyl-2-butanol, orisopropanol, and more preferably n-butanol.

The obtained darifenacin hydrobromide may have a purity of about 99% toabout 100% area by HPLC, preferably about 99.6%-99.85% area by HPLC, andmore preferably about 99.7% to about 99.8% area by HPLC.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one of ordinaryskill in the art from consideration of the specification. The inventionis further defined by reference to the following examples. It will beapparent to those of ordinary skill in the art that many modifications,both to materials and methods, may be practiced without departing fromthe scope of the invention.

EXAMPLES

HPLC Column & GEMINI C18 110A 250 mm × 4.6 mm × 5.0 μm Packing: (cat.No. 00G-4435-E0) from Phenomenex (or equivalent) Buffer: K₂HPO₄ 0.02 MpH 7.0: 3.48 g of K₂HPO₄ in 1000 ml of deionized water, adjust pH at 7.0± 0.2 with H₃PO₄ 15% (w/v). Filter on a 0.45 μm filter. Eluent A:Acetonitrile Time (min) % Buffer % Eluent A Gradient:  0 50 50 20 30 7030 30 70 Equilibrium time: 8 minutes Sample volume: 5.0 μl Flow Rate:1.0 ml/min Detector: UV at 215 nm Column 35° C. temperature: Diluent:H₂O:Acetonitrile (50:50)

Example 1 Preparation of 1-tosyl-3-(S)-(−)tosyloxypyrrolidine (FormulaI)

(S)-3-pyrrolidinol (30 g, 0.344 moles) was dissolved in toluene (150 ml)and tetrabutylammonium bromide (3.39 g, 0.0105 moles) was added to thesolution. p-Toluensulfonylchloride (140.94 g, 0.7393 moles) was thenadded portion-wise to the solution, causing the temperature of thesolution to rise to 35 to 40° C. Then, 30% NaOH (112.1 g, 0.8407 moles)was slowly added to the solution over about 1 hour, causing thetemperature of the solution to rise to 55 to 60° C. After maintainingthe solution for 5 hours at 55-60° C., the reaction was complete. Water(30 ml) was then added, and the resulting suspension was cooled to 0° C.over 1 hour to give a solid. The solid was filtered and washed with coldtoluene and water to give the title compound. (Dry weight 127.95 g,yield 94%, HPLC purity 99.2% area). The main impurity is1-tosyl-3-(S)-pyrrolidinol (reaction intermediate) in an amount of 0.05%area by HPLC.

Example 2 Preparation of(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile (Formula II)

Diphenylacetonitrile (63.7 g, 0.3296 moles) was dissolved in DMF (395ml), followed by adding sodium tert-butylate (31.75 g, 0.33 moles),which caused the temperature of the solution to rise to 35° C. Aftercooling the solution to 20° C., 1-tosyl-3-(S)-(−)tosyloxypyrrolidine(126.5 g, 0.3198 moles) was added. The solution was warmed to 70 to 75°C., and, after maintaining the solution at 70 to 75° C. for 4 hours, thereaction was complete. Water (250 ml) and toluene (500 ml) were thenadded to the solution to form a two phase mixture having an aqueous andan organic phase. The phases were stirred at 70° C. and separated. Theaqueous phase was extracted with toluene (50 ml), followed by washingthe combined organic phases three times with water (100 ml each), andconcentrating under vacuum to give a 250 ml residual volume. Theresidual volume was cooled to 0° C. to obtain a precipitate. Theprecipitate was filtered and washed with toluene and water to give thetitle compound. (Dry weight 116 g, yield 86.5%, and HPLC purity 99.3%area). The main impurities present are residual starting materials:diphenylacetonitrile and N—O-ditosyl-3-(S)-pyrrolidinol in amounts of0.1% area by HPLC each.

Example 3 Preparation of (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrileHydrobromide (S-DIPACP.HBr) (Formula III)

In a 2 l reactor equipped with mechanical stirrer, thermometer andcondenser HBr 48% (1.100 ml), Phenol (44.08 g), and S-DIPACP-N-Tosyl[(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile] (220 g) wereloaded under nitrogen. The suspension was warmed to reflux (118-120° C.)to obtain a biphasic system. After 1 hr, the reaction was complete(residual starting material 0.33%). The reaction mixture was then cooledto 25-30° C. and dichloromethane (478 ml) was added. After stirring (5min) the phases were separated (organic phase is upper layer) and theaqueous phase was extracted with dichloromethane (100 ml) and the phasesagain separated (organic phase is upper layer). The collected organicphases were concentrated to 280-290 ml by solvent distillation atatmospheric pressure to obtain an oily residue (T_(int) 64° C.).Maintaining internal temperature at 65-70° C. ethylacetate (287 ml) wasslowly added to the residue. (It is necessary to maintain temperatureand to add ethyl acetate slowly to avoid sudden productcrystallization). Distillation was continued at atmospheric pressure toreach a volume of 380-390 ml (T_(int) 80° C., T_(head) 70° C.). Ethylacetate (191 ml) was added to the obtained suspension and distillationwas continued at atmospheric pressure to reach a volume of 380-390 ml(T_(int) 84° C., T_(head) 72° C.). Repeated distillations are necessaryto eliminate as much dichloromethane as possible in such a way as toincrease yield. The suspension was cooled at 50-55° C. and ethyl acetate(300 ml) was added. The suspension was cooled to 20-25° C. and after 1hr, was cooled to −7-8° C. After 2 hrs, the suspension was filtered andwashed three times with cold ethyl acetate (95 ml) each. After washings,the product became white (initially it was pink). The wet product wasdried under vacuum at 50-55° C. for 6-7 hrs to obtain the titlecompound. (Dry weight 166.3 g, yield 87.4%, HPLC purity 99.93% area).

Example 4 (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile HydrobromideUsing β-Naphtol as Bromine Acceptor (Formula III)

(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile (5 g, 0.0120moles) was added to 48% HBr (25 ml) together with β-naphtol (1.73 g,0.0120 moles), to give a suspension. The suspension was warmed to reflux(117-120° C.), and, after 1 hour the reaction was complete. Aftercooling to 30° C., dichloromethane (10 ml) was added, and the mixturewas stirred for 5 minutes. The phases were separated, and the aqueousphase was extracted with dichloromethane (5 ml). The combined organicphases were washed with saturated solution of NaCl, and thenconcentrated under vacuum to give a residual volume of 10 ml.

Ethyl acetate (10 ml) was added to the residual volume, and thedistillation was continued at atmospheric pressure until a residualvolume of 8 ml was obtained. Ethyl acetate was added, and thedistillation continued until the dichloromethane was eliminated(residual volume 8 ml). Ethyl acetate (15 ml) and hexane (10 ml) wereadded to give a suspension. The suspension was cooled to 0° C. for 2hours to give a precipitate that was filtered and washed with ethylacetate to give the title compound. (Dry weight 3.0 g; yield 72.4%).

Example 5 Preparation of(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilehydrobromide (Formula III)

Potassium carbonate (14.94 g, 0.1081 moles) was dissolved in water (45ml), followed by adding (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrilehydrobromide (18.55 g, 0.0540 moles) and5-(2-bromoethyl)-2,3-dihydrobenzo[2,3-b]furan (13.5 g, 0.05945 moles) togive a suspension. The suspension was warmed to 75° C., and, after 4hours, the reaction was considered to be complete (unreacted startingmaterial 1.5% area by HPLC). The heterogeneous mixture was cooled to 25°C. and ethyl acetate (100 ml) was added. After stirring, the phases wereseparated, the organic layer was washed with water, and the phasesseparated. 48% hydrobromic acid (9.6 g, 0.05668 moles) was added, and(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilehydrobromide was crystallized from the suspension. The suspension wascooled to 15-18° C. for one hour, and the precipitate was filtered andwashed with ethyl acetate to give the title compound. (Dry weight 23.8g; yield 89.93%).

Example 6 Preparation of3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidineHydrobromide (Formula III)

KOH (1.95 g, 0.03134 moles) was added to 2-methyl-2-butanol (7 ml), toobtain a suspension. The suspension was warmed to 60° C. for 1 hour,followed by adding(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrilehydrobromide (1 g, 0.00204 moles), and warming the reaction mixture(suspension) to reflux for 21-22 hours. After cooling, water (5 ml) wasadded to the reaction mixture to form a two-phase mixture, and thephases were separated. The solvent was distilled from the organic phaseunder vacuum, and a residue (0.900 g) was obtained and dissolved inmethylethylketone (3 ml). The solution was filtered to eliminateundissolved solid, and 48% HBr (0.344 g, 0.00204 moles) was added. Thesolvent was distilled under vacuum, and a solid foam was obtained. Thefoam was slurried in diisopropylether, filtered, and washed to give thetitle compound. (Dry weight 0.750 g; yield 72%).

Example 7 Preparation of3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine Tartrate (FormulaVI)

3-(S)-(+)-(1-Cyano-1,1-diphenylmethyl)pyrrolidine hydrobromide (80 g0.2330 moles) was converted into its corresponding free base by treatingwith dichloromethane (400 ml), water (150 ml) and 30% NaOH (35 g). Afterphase separation and evaporation of the solvent from the organic phase,an oil residue was obtained. The oil residue was added to 90% H₂SO₄ (130ml), and the mixture was heated to 100° C. for 17 hours. After cooling,the mixture was neutralized with sulfuric acid until a pH of 12 wasobtained. The product was extracted with dichloromethane (250 ml). Afterwashings with water, the solvent was evaporated by distillation, and theproduct was obtained as a foam (45.7 g). The foam was dissolved in 96%ethanol (460 ml), and L-Tartaric acid (26.9 g) was added, followed bycooling to 0° C., to induce crystallization of the tartrate salt. Thesalt was filtered after 1 hour, and washed with 96% ethanol to give thetitle compound. (Dry weight 64.5 g; yield 64.5%).

Example 8 Preparation of 3-(S)-(+)-(1-carbamoyl-1diphenylmethyl)pyrrolidine Tartrate (Formula VI) a) Free BasePreparation

A four necked round bottomed flask equipped with a thermometer,mechanical stirrer and condenser was charged, under N₂, with3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine hydrobromide (96g), Dichloromethane (280 ml), and water (20 ml). The temperature wasmaintained at 25-30° C. during the loading of NaOH 30% (41.2 g). Theobtained heterogeneous system was stirred for 5 min. and the phases wereseparated. The organic phase was washed with water (41.2 ml), and thephases were separated. The organic phase was concentred under vacuumuntil a final volume of 120 ml was obtained.

b) Hydrolysis Reaction

A four necked round bottomed flask equipped with thermometer, mechanicalstirrer and condenser to eliminate dichloromethane by distillation, wascharged under N₂ with H₂SO₄ 90% (180 ml).

The sulfuric acid solution was warmed to 50-55° C., and the organicsolution obtained above (120 ml) was added slowly allowingdichloromethane elimination by distillation. During the addition themixture was warmed continuously to maintain an internal temperature of60-65° C. When dichloromethane distillation stopped, the internaltemperature was raised to 98-102° C. allowing residual dichloromethaneelimination by distillation. Then, the temperature was maintained at98-102° C. for 14-14.5 hrs.

The reaction mixture was cooled to 25-30° C. and added slowly to amixture of NaOH 30% (958.3 g), water (720 g), and toluene (480 ml),allowing the internal temperature to reach 55-60° C. After stirring at55-60° C. the phases were separated at 55-60° C. The aqueous phase wasbeen extracted at 55-60° C. with toluene (160 ml).

The collected organic phases, maintained at 60-65° C., were washed at60-65° C. with water 240 ml, and then n-butanol (200 ml), water (20 ml)and L-tartaric acid (42.05 g) were added to the separated organic phaseat 45-65° C. The mixture was stirred at 45-65° C. until the L-tartaricacid was almost completely dissolved. At the same time a formation of asalt was detected, at the beginning as a white oil, and then as whitesolid. The suspension was cooled to 15-25° C. and filtered after twohours. When the suspension was too sticky it was found useful to warm to60-65° C. and after 10-15 min to cool to 15-25° C. and filter. The cakewas washed three times with n-butanol (50 ml each), and after 15 hrs ofdrying at 50-55° C. under vacuum 107 g of the title compound wasobtained. (Yield: 88.9%. HPLC purity: 99.88% area).

Example 9 Preparation of 2(2,3-Dihydrobenzofura-5-y)acetic Acid, MethylEster

98% H₂SO₄ (2 g) was added to a solution of2(2,3-Dihydrobenzofura-5-y)acetic acid (200 g) in MeOH (500 ml), and themixture was refluxed for 3 hrs (TLC: SiO₂, toluene/AcOEt 8:2; startingmaterial not detected). After cooling to room temperature, NaHCO₃ (6.7g) was added to the reaction mixture, and the solvent was distilled offat atmospheric pressure (about 440 ml), to give a light pink oilyresidue.

The oily residue was dissolved in toluene (250 ml), and washed withNaHCO₃ 6% (50 ml). After the phases were separated, the solvent waseliminated under vacuum distillation to obtain a light pink oily residue(227 g).

Example 10 Preparation of 2(2,3-Dihydrobenzofura-5-y) Ethanol

2(2,3-Dihydrobenzofura-5-y)acetic acid, methyl ester (227 g residue) wasdissolved in t-BuOH (600 ml), and then NaBH₄ (46.8 g) was added. Thesuspension was warmed to reflux and methanol (100 ml) was added veryslowly in about 6 hrs maintaining reaction mixture at reflux. After themethanol addition, the reaction was maintained at reflux for half anhour (In process control revealed complete ester transformation. 400 mlof the t-BuOH-MeOH mixture was distilled off at atmospheric pressure.Water (400 ml) was added to residue and the distillation continued untilT_(int)=93° C. and T_(head)=83° C. Water (400 ml) was added, and thedistillation continued until T_(int)=96° C. and T_(head)=96° C. Thereaction mixture was cooled to 70-75° C. and toluene (300 ml) was added.The separated organic phase was washed with water (100 ml) and NaCl 15%(100 ml). After the solvent was eliminated under vacuum distillation, anoily residue (176.8 g) of the title compound was obtained. The residuesolidified upon cooling.

Example 11 2(2,3-Dihydrobenzofuran-5-y) Ethylchloride

SOCl₂ (74.7 g) was added to a solution of 2(2,3-Dihydrobenzofura-5-y)ethanol 80 g in toluene (400 ml) while maintaining the temperature below25° C. The reaction mixture was stirred at 60° C. for 14 h and thencooled to room temperature. A reaction sample was quenched into 10%Na₂CO₃ (Residual 2(2,3-Dihydrobenzofura-5-y) ethanol 0.6% area by HPLC),and the pH was adjusted to 10-11 (measured on aqueous phase) by additionof 10% NaOH (about 480 ml) while maintaining the temperature below 30°C. The organic phase was separated. The aqueous phase was extracted withtoluene (50 ml). The collected organic phases were washed twice with H₂O(100 ml each) and anhydrified under vacuum distillation (residualpressure 40-50 mm Hg, T_(int) 50-55° C.). To the organic phase, 20 g ofTONSIL® silicate decolorizing agent and 4.2 g of ANTICHROMOS charcoalwere added, stirred for 30 min at room temperature, filtered off andwashed with toluene (2×30 ml), the decolorized solution was concentratedunder vacuum (residual pressure 40-50 mm Hg, T_(int) 50-55° C.) toeliminate toluene. Water (25 ml) was added to obtain a residue, and theresidual toluene was eliminated by azeotropic distillation under vacuum(residual pressure 40-50 mm Hg, T_(int) 50-55° C.). This residue wasdissolved in methanol (373 ml) and charcoal (2 g) was added. After 20minutes at 50-55° C. charcoal was filtered off and washed with hotmethanol (2×10 ml). The obtained decolorized solution was cooled at20°-30° C., and 2(2,3-Dihydrobenzofuran-5-y) ethylchloride crystallizedin the suspension. Water (280 ml) was added to the suspension at 25°-30°C. over about 60 min to obtain a sticky, but stirrable, suspension.After 1 hr at 20-25° C. the solid was filtered, and washed three timeswith MeOH-Water 1:1 (20 ml each). The wet solid was dried at 35-40° C.max for 15 hrs to give the title compound. (Dry weight 81.8 g. Yield92%. HPLC purity 99.2% area).

Example 12 Preparation of (S)-Darifenacin Hydrobromide

A 50 ml reactor was loaded with-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate (4 g, 9.29mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchloride (1.95 g, 10.68mmoles), potassium carbonate (6.14 g, 44.42 mmoles), and water (12.5ml), to obtain a heterogeneous mixture. The heterogeneous mixture washeated to reflux (103° C.) for 2.5 hours. After cooling,dichloromethane, EtOAc or BuOAc (15 ml) were added, and, after stirring,the phases were separated. Acetic anhydride (0.5 ml) was added to theorganic phase, and, after 1 hour at room temperature, the residual3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine was transformedinto N-Acetyl derivative. The solvent was removed by distillation, andn-butanol (25 ml) was added to the residue. 48% hydrobromic acid (1.72g) was also added, and the residual DCM was removed under vacuumdistillation. In the case of EtOAc or BuOAc, distillation under vacuumis useful to eliminate water. Darifenacin hydrobromide crystallized,and, after cooling to room temperature, the darifenacin hydrobromide wasfiltered and washed. (Wet solid 4.17 g).

Example 13 Preparation of (S)-Darifenacin Hydrobromide

A 50 ml reactor was loaded with(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine free base (2.6 g,9.29 mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchloride (1.95 g, 10.68mmoles), potassium carbonate (6.14 g, 44.42 mmoles), and water (12.5 ml)to obtain a heterogeneous mixture. The heterogeneous mixture was heatedto reflux (103° C.) for 2 to 5 hours. After cooling, dichloromethane,Ethyl acetate, or Butylacetate (15 ml) was added, and, after stirring,the phases were separated. Acetic anhydride (0.5 ml) was added to theorganic phase, and, after 1 hour at room temperature, the residual3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine was transformedinto N-Acetyl derivative (as described in example 11). Half of thesolvent was removed by distillation, and n-butanol (25 ml) was added tothe residue. 48% hydrobromic acid (1.72 g) was also added, and theresidual DCM was removed under vacuum distillation. In the case of EtOACor BuOAc, distillation under vacuum is useful to eliminate water.Darifenacin hydrobromide crystallized, and, after cooling to roomtemperature, the darifenacin hydrobromide was filtered and washed. (Drysolid 2.5 g).

Example 14 Preparation of (S)-Darifenacin Hydrobromide

A 150 ml reactor was loaded with water (37.5 ml), potassium carbonate(12 g), and 2(2,3-Dihydrobenzofuran-5-yl-ethylchloride (DBF-EtCl) (5.48g). The mixture was warmed to 60-65° C. and DBF-EtCl melted. Then,(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate (12 g) wasloaded and the heterogeneous mixture was warmed to reflux (101-102° C.)for 5 hrs.

The reaction mixture was cooled to 80-85° C. and n-butanol (60 ml) wasadded. The internal temperature was maintained at 75-80° C., and themixture was stirred until complete dissolution was obtained. Then, themixture was cooled to 25-30° C. and the phases were separated. Theorganic phase was washed twice with water (30 ml) and the phases wereseparated.

Water was removed by vacuum distillation until a residual volume of 60ml was obtained, and then n-butanol (30 ml) was added. Then, aceticanhydride (0.6 ml) was loaded and the mixture was stirred at 20-30° C.for 1 hr, followed by loading HBr 48% (4.7 g) at 25-27° C. The water and20 ml of butanol were removed by vacuum distillation to obtain asuspension of darifenacin hydrobromide. The suspension was stirred at25-30° C. for 2 hrs, and then cooled to 0-5° C., and filtered after 1hr. The cake was washed with cold n-Butanol (3×3 ml), and dried undervacuum at 50-55° C. for 6-7 hrs. (Dry weight 11.2-11.5. Yield 79-81%).

Example 15 Crystallization of (S)-darifenacin Hydrobromide

A 100 ml reactor was loaded with crude darifenacin hydrobromide (10 g),n-butanol (70 ml), and charcoal (0.3 g). The mixture was warmed toreflux to obtain a solution. The charcoal was filtered at reflux andwashed with n-butanol (5 ml).

The solution was maintained at 100° C. and seeded to inducecrystallization. After 30 min at 100° C., the mixture was cooled to 0°C. over 3 hrs, and after 1 hr at 0° C. the mixture was filtered. Theproduct was washed with cold butanol (3×3 ml). (Dry weight 8.8-8.9 g.Yield 88-89%. HPLC purity 99.65-99.75% area).

Example 16 Preparation of (S)-Darifenacin Hydrobromide Via(S)-Darifenamine

3-(S)-(+)-(1-Carbamoyl-1,1-diphenylmethyl)pyrrolidine (2.1 g, 7.5mmoles) and 2,3-dihydrobenzofuran-5-yl,acetaldehyde (1.4 g, 8.6 mmoles)were combined with toluene (20 ml) at room temperature, and reacted for15 hours to give (S)-darifenamine.

At this point, a solution of NaBH₄ (0.57 g, 15 mmoles) in ethanol (10ml) was added slowly, and after 3 hours at room temperature, HPLCanalysis revealed formation of (S)-Darifenacin. After washing withwater, the solvent was eliminated by distillation, and the obtainedresidue was dissolved in n-BuOH followed by the addition of HBr 48% (1.5g, 9 mmoles). Water was eliminated under vacuum, and a slowcrystallization was observed. After cooling, the product was filteredand washed with n-BuOH to give the title compound. (Dry weight 0.7 g).

The same reaction has been performed in presence of molecular sieves andtitanium isopropylate with similar results.

Example 17 Purification of Darifenacin HBr

The product of Example 16 (3.6 g) was suspended in n-Butanol (25 ml),and heated to reflux to obtain a solution. Charcoal (0.1 g) was added,and, after 5 minutes at reflux, was filtered off. After cooling to roomtemperature, Darifenacin HBr was filtered, washed, and dried at 45-50°C. under vacuum for 10 hours. (Dry solid 3.20 g; overall yield 68%; HPLCpurity 99.86% area).

Example 18 2,3-Dihydrobenzofura-5-yl, acetaldehyde

In a four necked round bottomed flask equipped with thermometer,mechanical stirrer and condenser, was charged under N₂,2,3-Dihydrobenzofura-5-yl, carboxaldehyde (50 g, 0.33 moles) and2-butylchloroacetate (66.5 g, 0.4415 moles). The solution was warmed to40-45° C., followed by a dropwise addition (in about 1 hour) of 288 mlof 17% (w/v) potassium 2-butylate solution in 2-butyl alcohol (0.43moles). The reaction was maintained at a temperature of 40-45° C., andafter 1 hour at 40-45° C., HPLC analysis revealed almost completetransformation of carboxaldehyde. The suspension was slowly added to asolution of KOH 90% (24.5 g, 0.3937 moles) in water (47 ml), followed bymaintaining at 45-50° C. After 1 hour at 45° C., TLC analysis revealedcomplete hydrolysis, and a thick suspension was obtained. At this pointtoluene (120 ml) and water (180 ml) were added, and the suspension wascooled to 1-5° C. Then, 75% H₃PO₄ (about 50 g) was added drop-wise toobtain a pH in range of 5.4-5.8. During acidification CO₂ evolves andalmost complete solid dissolution is observed. After the phases areseparated, the organic phase was washed with water (200 ml) and thenwith sat NaCl, (100 ml). After solvent elimination under vacuum, aresidual oil (47 g) of the title compound was obtained.

Example 19 2(2,3-Dihydrobenzofura-5-y) acetaldehyde, bisulfitic complex

In a four necked round bottomed flask equipped with thermometer, andmechanical stirrer, was loaded 2,3-Dihydrobenzofura-5-yl, acetaldehyde,of example 18 (47 g, 0.29 moles) and toluene (500 ml) to obtain asolution. Then, water (100 ml) and Na₂S₂O₅ (58.6 g) were added. Thebisulfitic adduct precipitated and after 3 hours at room temperature itwas filtered and washed twice with toluene (50 ml each). (Wet product:95 g).

Example 20 2(2,3-Dihydrobenzofura-5-y) Ethanol

The obtained wet bisulphitic adduct of example 19 was suspended in water(150 ml), and the pH was adjusted to 10-10.2 with NaOH 30%. Na₂CO₃ 10%(50 ml) and toluene (100 ml) were added and, after cooling to 5-10° C.,a solution of NaBH₄ (5.8 g, 0.1526 moles)) in water (40 ml) was addeddrop-wise over about 45-60 minutes, while maintaining the pH at9.8-10.2. The temperature was raised to 15-20° C. and after 1 hour thephases were separated. The aqueous phase was extracted with toluene (25ml), and the combined organic phases were washed with water (50 ml). Thesolvent was eliminated under vacuum distillation, and the obtained oilsolidified to give the title compound (26 g).

Example 21 Preparing 5-(2-chloroethyl)-2,3-dihydrobenzofuran of FormulaII in DMF, Toluene and in a Mixture of Dimethylformamide (DMF) andToluene

Level of 2- Level of 5-(2- (benzofuran-5- chloroethyl)-2,3- Temperatureyl)ethanol of formula benzofuran of formula Solvent (° C.) V (area % byHPLC) I (area % by HPLC) DMF 20° C. nd 0.3 DMF 0-5° C.  ndv 0.44Toluene/ 55° C. 0.01 1.15 DMF 99:1 Toluene 60° C. 0.03 0.21 Toluene 60°C. nd 0.19 Toluene 60° C. nd 0.14 * nd = not determined

Example 22 Correlation Between the Levels of the Oxidized Impurities inthe Intermediates for Preparing Darifenacin Hydrobromide to the Level ofOxidized Darifenacin

Level of Level of Level of impurity Level of impurity impurity Level of(area % by impurity (area (area (area % impurity (w/w HPLC) % by HPLC) %by HPLC) by HPLC) % by HPLC) BF—AcOH BF—AcOMe BF-EtOH BF-EtCl Oxidizeddarifenacin 0.18 0.17 0.16 0.18 0.09 0.50 0.53 0.47 0.30 0.49 * BF—AcOHis benzofuran-5-acetic acid; BF—AcOMe is benzofuran-5-methylester aceticacid; BF-EtOH is benzofuran-ethanol; and BF-EtCl is5-(2-chloroethyl)-benzofuran.

Comparative Example 23 Example 1 from U.S. Pat. No. 5,096,890 (col. 6,l. 56 to col. 7, l. 51) (A) Preparation of3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine

A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine(0.33 g—see Preparation 8), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.25g—see Preparation 13), anhydrous potassium carbonate (0.3 g) andacetonitrile (10 ml) was heated under reflux for 2 hours. The mixturewas partitioned between dichloromethane (50 ml) and 10% aqueouspotassium carbonate (10 ml), the layers were separated, and the aqueouslayer extracted with dichloromethane (3×20 ml). The combineddichloromethane extracts were dried (MgSO₄) and concentrated in vacuo toleave a gum which was purified by column chromatography on silicaeluting with dichloromethane containing methanol (0% up to 8%). Theproduct-containing fractions were combined and concentrated in vacuo toleave an oil which was crystallised from diisopropyl ether to give thetitle compound as a colourless powder, yield 0.17 g, m.p. 131°-132° C.

Analysis %: Found: C, 78.90; H, 7.70; N, 6.28. Calculated forC₂₈H₃₀N₂O₂: C, 78.84; H, 7.90; N, 6.57.

¹H N.m.r. (CDCl₃) δ=7.50-7.20 (m, 11H); 7.00 (s, 1H); 6.90 (d, 1H); 6.70(d, 1H); 5.45-5.30 (brs, 1H); 4.60-4.50 (t, 2H); 3.60-3.45 (m, 1H);3.25-3.15 (t, 2H); 3.05-2.50 (m, 8H); 2.10-1.95 (m, 2H) ppm.

(B) A similar procedure starting with3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (1.95 g—seePreparation 10(B)) gave3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidineas a foam, yield 1.9 g, [α]_(D) ²⁵ −20.6° (c 1.0, CH₂Cl₂).

(C) A similar procedure starting with3-(R)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (2.8 g—seePreparation 11) gave3-(R)-(+)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidineas a foam, yield 1.7 g, [α]_(D) ²⁵ +18.1 (c 1.0, CH₂Cl₂).

While it is apparent that the invention disclosed herein is wellcalculated to fulfill the objects stated above, it will be appreciatedthat numerous modifications and embodiments may be devised by thoseskilled in the art. Therefore, it is intended that the appended claimscover all such modifications and embodiments as falling within the truespirit and scope of the present invention.

1. A process for preparing darifenacin hydrobromide, comprisingconverting N-protected-3-(S)-pyrrolidinol of the formula

into darifenacin hydrobromide, wherein X is S, SO₂, Si, or CO, and R isphenyl, tolyl, ortho, meta, or para-xylyl, linear or branched C₁₋₁₀alkyl, H, or CF₃.
 2. The process according to claim 1, wherein theconversion comprises preparing1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I

in a process comprising combining 3-(S)-(+)-hydroxypyrrolidine, asulfonyl halide, a base, and a solvent selected from the groupconsisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organicsolvent, and mixtures thereof to obtain1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine, wherein X is eitherC₁₋₁₀ alkyl or C₆₋₉ aryl.
 3. The process of claim 2, wherein X is tolyl.4. The process of claim 2, wherein the solvent is selected from a groupconsisting of C₆₋₉ aromatic hydrocarbon, C₁₋₁₀ halogenated aliphatichydrocarbon, amide, sulfoxide, and mixtures thereof.
 5. The process ofclaim 4, wherein the solvent is selected from a group consisting oftoluene, o-xylene, m-xylene, p-xylene, dichloromethane,1,2-dichloroethane, dichloropentane, dimethylformamidemDimethylacetamide, dimethylsulfoxide, and mixtures thereof.
 6. Theprocess of claim 2, wherein the process, further comprises a phasetransfer catalyst.
 7. The process of claim 6, wherein the phase transfercatalyst is selected from the group consisting of tetrabutylammoniumbromide, tributylmethylammonium chloride, tetrabutylammonium sulfate,and dimethylsulfoxide.
 8. The process of claim 2, wherein the halidemoiety of the sulfonyl halide is selected from chloride, bromide, andiodide.
 9. The process of claim 8, wherein the sulfonyl halide istosylchloride, mesylchloride, or brosylchloride.
 10. The process ofclaim 2, wherein the base is an organic base.
 11. The process of claim10, wherein the organic base is selected from the group consisting ofaliphatic and aromatic amines.
 12. The process of claim 11, wherein theorganic base is selected from a group consisting of triethylamine,methylmorpholine, N,N-diisopropylethyl amine, pyridine and mixturesthereof.
 13. The process of claim 2, wherein the base is an inorganicbase.
 14. The process of claim 13, wherein the inorganic base is analkali base.
 15. The process of claim 14, wherein the alkali base issodium hydroxide or potassium hydroxide.
 16. The process of claim 2,further comprising recovering the1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine.
 17. The processaccording to claim 1, wherein the conversion comprises preparing(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil) acetonitrile of formulaII

in a process comprising combining1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I,

diphenylacetonitrile, and an inorganic base in an organic solventselected from the group consisting of a C₆₋₉ aromatic hydrocarbon, apolar aprotic organic solvent, and mixtures thereof, and an inorganicbase to obtain(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile, wherein Xis either C₁₋₁₀ alkyl or C₆₋₉ aryl.
 18. The process of claim 17, whereinX is tolyl.
 19. The process of claim 17, wherein the solvent is selectedfrom a group consisting of C₆₋₉ aromatic hydrocarbon, amide, andsulfoxide.
 20. The process of claim 19, wherein the solvent is selectedfrom a group consisting of C₁₋₂ amide, dimethylformamide,dimethylacetamide, C₁₋₄ sulfoxide, dimethylsulfoxide and mixturesthereof.
 21. The process of claim 17, wherein the inorganic base is ametal alkoxide or an alkali hydroxide.
 22. The process of claim 21,wherein the inorganic base is selected from a group consisting of sodiumtert-butoxide, potassium tert-butoxide, sodium methoxide, sodiumhydroxide, and potassium hydroxide.
 23. The process of claim 17, furthercomprising recovering the(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile.
 24. Theprocess according to claim 1, wherein the conversion comprises preparing3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate offormula VI

in a process comprising: a. combining(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

a solvent selected from the group consisting of a water immiscibleorganic solvent, a polar aprotic organic solvent, water, and mixturesthereof, and an inorganic base to form a mixture; b. acidifying themixture; c. heating the mixture; d. basifying the mixture; and e.combining the mixture with a C₁₋₄ alcohol and L-tartaric acid to obtain3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate, whereinZ1 is an acid.
 25. The process of claim 24, wherein Z₁ is HBr or HCl.26. The process of claim 24, wherein the(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III isconverted into the free base of formula XI

prior to step b).
 27. The process of claim 26, wherein the(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III isconverted into the free base of formula XI by combining the(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III asolvent selected from the group consisting of water immiscible organicsolvents, a polar aprotic organic solvent, water, and mixtures thereof,and an inorganic base.
 28. The process of claim 24, wherein the solventis selected from a group consisting of C₆₋₉ aromatic hydrocarbon, water,C₁₋₁₀ halogenated aliphatic hydrocarbon, ester, and mixtures thereof.29. The process of claim 28, wherein the solvent is selected from agroup consisting of toluene, xylenes, isopropylbenzene, styrene, water,dichloromethane, 2-dichloroethane, 1,1,-dichloroethane,1,5-dichloropentane, ethyl acetate and mixtures thereof.
 30. The processof claim 28, wherein the solvent is a mixture of a C₁₋₁₀ halogenatedaliphatic hydrocarbon and water.
 31. The process of claim 30, whereinthe C₁₋₁₀ halogenated aliphatic hydrocarbon is dichloromethane.
 32. Theprocess of claim 24, wherein the acidifying comprises adding an acid tothe mixture and heating the mixture.
 33. The process of claim 32,wherein the strong mineral acid is sulphuric acid or phosphoric acid.34. The process of claim 32, wherein the mixture is heated to atemperature of about 80° C. to about 110° C.
 35. The process of claim24, wherein the mixture is basified to a pH of about 10 to about
 13. 36.The process of claim 24, wherein the mixture is basified by adding aninorganic base.
 37. The process of claim 36, wherein the inorganic baseis an aqueous solution of an alkali base.
 38. The process of claim 37,wherein the alkali base is selected from a group consisting of sodiumhydroxide, potassium hydroxide sodium carbonate, potassium carbonate,sodium bicarbonate, potassium bicarbonate and mixtures thereof.
 39. Theprocess of claim 24, wherein the C₁₋₄ alcohol is methanol, ethanol,isopropanol, or n-butanol.
 40. The process of claim 24, furthercomprising recovering the3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate offormula VI.
 41. A process for preparing darifenacin hydrobromidecomprising: a) combining 3-(S)-(+)-hydroxypyrrolidine, a solventselected from the group consisting of a C₆₋₉ aromatic hydrocarbon, apolar aprotic organic solvent, and mixtures thereof, a sulfonyl halide,and a base to obtain 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I,

b) reacting the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine offormula I with diphenylacetonitrile and an inorganic base in an organicsolvent selected from the group consisting of a C₆₋₉ aromatichydrocarbon, a polar aprotic organic solvent, and mixtures thereof toobtain (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile offormula II;

c) reacting the (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile intermediate of formula II with a bromine acceptor selectedfrom the group consisting of phenol and naphthol and an acid to obtain(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

wherein the bromine acceptor is phenol only when the acid is HBr; d)combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt offormula III and an inorganic base with a solvent selected from the groupconsisting of water immiscible organic solvent, a polar aprotic organicsolvent, water, and mixtures thereof to form a mixture; e) acidifyingthe mixture; f) heating the mixture g) basifying the mixture; h)combining the mixture with a C₁₋₄ alcohol and L-tartaric acid to obtain3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate offormula VI;

i) converting 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidinetartrate of formula VI to Darifenacin hydrobromide.